PROJECT 1 PROJECT SUMMARY / ABSTRACT Alzheimer s disease (AD) pathology can be observed in the brain many years or even decades before the onset of the resulting dementia providing a window of opportunity where intervention may have the greatest chance of success. Observed alterations in this prodromal stage involve multiple distinguishable neural networks in the brain, including the medial temporal and parietal lobe networks. Particularly, increased hippocampal activation observed with functional magnetic resonance imaging (fMRI) in subjects with mild cognitive impairment (MCI) appears to contribute to memory dysfunction and may therefore potentially be used as a marker for the early development of AD pathology. However, it remains unclear if this hippocampal sub region specific dysfunction is associated with other fMRI changes commonly observed in the early stages of the disease, such as parietal network changes or functional connectivity changes between medial temporal and parietal lobe networks. Additionally, it remains unclear how these fMRI changes relate to established biomarkers of AD pathology such as cerebrospinal fluid (CSF) measures of A, tau and p-tau. Finally, it remains unclear if hippocampal, parietal or functional connectivity changes can be observed in cognitively normal individuals who have a significant memory concern and may represent an even earlier phase along the AD continuum. The current project proposes to directly address these questions in a high-resolution neuroimaging study of hippocampal and parietal network function, examining functional connectivity between these networks and their association with CSF measures of A, tau and p-tau in subjects along the prodromal continuum of AD. Targeted fMRI activation tasks will be employed designed to tax hippocampal sub region specific function and parietal network function. High-resolution resting state fMRI will be employed to assess connectivity changes between hippocampal and parietal networks. CSF samples will be collected to assess the relationship between these network changes and CSF measures of A, tau and p-tau. These methods will be employed in four groups of subjects: (1) cognitively normal subjects with subjective memory concerns (SMC), (2) subjects with early MCI (EMCI), (3) late MCI (LMCI), and (4) healthy control subjects. Together the proposed studies will provide insight into the functional brain changes associated with hippocampal and parietal network dysfunction and functional connectivity between these networks in LMCI and EMCI subjects, compared to controls, and determine whether SMC subjects display similar abnormalities. These studies will thus shed light on the relationship between changes in these neural networks, cognitive performance and the accumulation of AD pathology in the brain in subjects across the early spectrum of disease. Finally, this work may provide evidence of whether fMRI measures of hippocampal network dysfunction can serve as a marker for the early development of AD pathology.